1. Field of the Invention
The present invention relates to a novel method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides.
2. Description of Related Art
It is well established that agents which inhibit the transport of bile acids across the ileum can also cause a decrease in the level of cholesterol in blood serum. Stedronski, in xe2x80x9cInteraction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,xe2x80x9d Biochimica et Biophysica Acta, 1210 (1994) 255-287, discusses biochemistry, physiology, and known active agents affecting bile acids and cholesterol.
A class of ileal bile acid transport-inhibiting compounds which was recently discovered to be useful for influencing the level of blood serum cholesterol is tetrahydrobenzothiepine-1,1-dioxides (THBDO compounds). (U.S. patent application Ser. No. 08/816,065=WO96/08484).
Some classes of compounds show enhanced potency as pharmaceutical therapeutics after they have been enantiomerically-enriched (see, for example, Richard B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, 1992, pp. 76-82). Therefore, THBDO compounds that have been enantiomerically-enriched are of particular interest.
A class of chemistry useful as intermediates in the preparation of racemic THBDO compounds is tetrahydrobenzothiepine-1-oxides (THBO compounds). THBDO compounds and THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring. A method of preparing enantiomerically-enriched samples of another phenyl/seven-member fused ring system, the benzothiazepines, is described by Higashikawa (JP 59144777), where racemic benzothiazepine derivatives are optically resolved on a chromatographic column containing chiral crown ethers as a stationary phase. Although optical resolution is achieved, the Higashikawa method is limited to producing only small quantities of the enantiomerically-enriched benzothiazepine derivatives.
Giordano (CA 2068231) reports the cyclization of (2S,3S)-aminophenylthiopropionates in the presence of a phosphonic acid to produce (2S,3S)-benzothiazepin-4-ones. However, that preparation is constrained by the need to use enantiomerically-enriched starting materials rather than racemic starting materials. In addition, the Giordano method controls the stereochemistry of the seven-member ring of the benzothiazepin-4-one only at the 2- and 3-positions. The 4-and 5-positions of the seven-member ring of the benzothiazepin-4-one are not asymmetric centers, and the stereochemistry at these sites therefore cannot be controlled by the Giordano method.
A method by which enantiomerically-enriched 1,5-benzothiazepin-3-hydroxy-4(5H)-one compounds have been produced is through the asymmetric reduction of 1,5-benzothiazepin-3,4(2H,5H)-dione compounds, reported by Yamada, et al. (J. Org. Chem. 1996, 61 (24), 8586-8590). The product is obtained by treating the racemic 1,5-benzothiazepin-3,4(2H,5H)-dione with the reaction product of an optically active alpha-amino acid and a reducing agent, for example sodium borohydride. Although a product with high optical purity was achieved, the method is limited by the use of a relatively expensive chemical reduction step.
The microbial reduction of racemic 1,5-benzothiazepin-3,4(2H,5H)-dione compounds to produce enantiomerically-enriched 1,5-benzothiazepin-3-hydroxy-4(5H)-one compounds is reported by Patel et al., U.S. Pat. No. 5,559,017. This method is limited by the inherent problems of maintaining a viable and pure bacterial culture of the appropriate species and variety. In addition, that method is limited in scale, producing only microgram quantities of the desired product.
Until now, there have been no reported processes for preparing enantiomerically-enriched THBDO compounds or enantiomerically-enriched THBO compounds. Furthermore, there have been no reported processes for controlling the stereochemistry at the 4- and 5-positions of the seven-member rings of THBDO compounds or THBO compounds.
A convenient and cost-effective method for preparing enantiomerically-enriched THBDO compounds and intermediates in the preparation thereof is of great importance and utility. In response to the need therefor, the present inventors have developed a method for preparing enantiomerically-enriched tetrahydrobenzothiepine-1-oxides or enantiomerically-enriched tetrahydrobenzo-thiepine-1,1-dioxides with chiral centers at the 4- and 5-positions of the seven-member ring.
Accordingly, among its various aspects, the present invention provides a method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide having the formula (I): 
wherein:
R1 and R2 are independently selected from among H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl;
R3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR24, SR15, S(O)R15, SO2R15, and SO3R15, wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR19, NR19R20, SR19, S(O)R19, SO2R19, SO3R19, NR19OR20, NR19NR20R21, NO2, CO2R19, CN, OM, SO2OM, SO2NR19R20, C(O)NR19R20, C(O)OM, COR19, P(O)R19R20, P+R19R20R21Axe2x88x92, P(OR19)OR20, S+R19R20A13, and N+R15R17R18Axe2x88x92,
wherein:
Axe2x88x92 is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation;
said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, CO2R13, CN, oxo, CONR13R14, N+R13R14R15Axe2x80x94, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R13R14, P+R13R14R15Axe2x88x92, and P(O)(OR13)OR14, and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR13, N+R13R14Axe2x80x94, S, SO, SO2, S+R13Axe2x80x94, PR13, P(O)R13, P+R13R14Axe2x80x94, or phenylene;
R19, R20, and R21 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, polyether, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclealkyl, heterocyclealkyl, heteroarylalkyl, quaternary heterocyclealkyl, alkylammoniumalkyl, carboxyalkylaminocarbonylalkyl, and quaternary heteroarylalkyl,
wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR15, N+R15R16Axe2x80x94, S, SO, SO2, S+R15Axe2x88x92, PR15, P+R15R16Axe2x80x94, P(O)R15, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
R19, R20, and R21 are optionally substituted with one or more groups selected from the group consisting of hydroxy, amino, sulfo, carboxy, sulfoalkyl, carboxyalkyl, sulfoalkyl, alkyl, heterocycle, heteroaryl, quaternary heterocyclealkyl, quaternary heteroarylalkyl, guanidinyl, quaternary heterocycle, quaternary heteroaryl, OR15, NR15R16, N+R15R17R18Axe2x88x92, SR15, S(O)R15, SO2R15, SO3R15, oxo, CO2R15, CN, halogen, CONR15R6, S2OM, SO2NR15R16, PO(OR22)OR23, P+R15R16R17Axe2x80x94, S+R15R16Axe2x80x94, and C(O)OM,
wherein R22 and R23 are independently selected from the substituents constituting R15 and M, or
R20 and R21, together with the nitrogen atom to which they are attached, form a cyclic ring;
R24 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;
R13 and R14 are independently selected from the group consisting of hydrogen and alkyl;
R15 and R16 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboalkylamino, heteroarylalkyl, heterocyclealkyl, and alkylammoniumalkyl; and
R17 and R18 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR15, NR15R16, SR15, S(O)R15, SO2R15, SO3R15, CO3R15, CN, halogen, oxo, and CONR15R16, wherein R15 and R16 are as defined above, or
R17 and R18 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; and
R4, R5, R6, and R7 are independently selected from among H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, alkoxy, aryloxy, xe2x80x94NO2, and xe2x80x94NR9R10; R and R10 are independently selected from among H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, butoxycarbonyl, and carbobenzyloxy;
R3 and the hydroxyl at the 4-position of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide are in a syn-conformation with respect to each other; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl can be optionally substituted with one or more moieties selected from among alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, xe2x80x94NO2, and halo; and
the sulfur at the 1-position of the seven-member ring and the carbon atoms at the 4-position and the 5-position of the seven member ring are chiral centers.
The method comprises cyclizing an enantiomerically-enriched aryl-3-propanalsulfoxide having the formula (II): 
wherein R1, R2, R3, R4, R5, R6, and R7 are as described above, and wherein the sulfur is a chiral center, to form the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide.
In another embodiment, the present invention also provides a method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide having the formula (I), wherein the method comprises oxidizing an aryl-3-hydroxypropylsulfide having the formula (IV): 
wherein R1, R2, R3, R4, R5, R6, and R7 are as described above, and wherein the oxidation is performed under enantioselective oxidation conditions to produce an enantionmerically-enriched aryl-3-hydroxypropylsulfoxide having formula (III): 
wherein R1, R2, R3, R4, R5, R6, and R7 are as described above, and the sulfur is a chiral center; oxidizing the 3-hydroxyl group of the enantionmerically-enriched aryl-3-hydroxypropylsulfoxide to produce an enantiomerically-enriched aryl-3-propanalsulfoxide having the formula (II); and cyclizing the enantionmerically-enriched aryl-3-propanalsulfoxide to form the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide.
In yet another embodiment, the present invention also provides a method of preparing an enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide having the formula (VII): 
wherein R1, R2, R3, R4, R5, R6, and R7 are as described above, R3 the hydroxyl at the 4-position of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide are in a syn-conformation with respect to each other, and the carbons at the 4-position and the 5-position of the seven member ring are chiral centers. The method comprises oxidizing an aryl-3-hydroxypropylsulfide having the formula (IV) under enantioselective oxidation conditions to produce an enantiomerically-enriched aryl-3-hydroxypropylsulfoxide having the formula (III) and having a chiral center at the sulfur; oxidizing the enantiomerically-enriched aryl-3-hydroxypropyl-sulfoxide to produce an enantiomerically-enriched aryl-3-propanalsulfoxide having the formula (II); cyclizing the enantiomerically-enriched aryl-3-propanalsulfoxide to form an enantiomerically-enriched tetrahydrobenzothiepine-1-oxide having the formula (I) and having chiral centers at the sulfur at the 1-position of the seven-member ring and at the carbons at the 4-position and the 5-position of the seven member; and oxidizing the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide to the enantiomerically-enriched tetrahydrobenzothiepine-1,1-dioxide.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
In still another embodiment, the present invention provides an ileal bile acid transport-inhibiting compound (IBAT inhibitors) useful for the prophylaxis or treatment of cardiovascular disease including hypercholesterolemia and atherosclerosis, said IBAT inhibitor compound having the structure of formula ((4R,5R)-XXVII): 
In still another embodiment, the present invention provides an ileal bile acid transport-inhibiting compound (IBAT inhibitors) useful for the prophylaxis or treatment of cardiovascular disease including hypercholesterolemia and atherosclerosis, said IBAT inhibitor compound having the structure of formula ((4S,5S)-XXVII): 